Acetaminophen interactions to avoid

Acetaminophen is classified as an analgesic and is the active ingredient in products like brand-name Tylenol and is used as a pain reliever and as an antipyretic. It does not reduce inflammation, unlike non-steroidal anti-inflammatory drugs (NSAIDs). Acetaminophen can be found as a single-ingredient product but is often combined with over 200 over-the-counter (OTC) medications to relieve pain and symptoms related to allergies and viral illnesses like the common cold or flu. Acetaminophen is an effective pain reliever and fever reducer for all age ranges, from pediatrics to older adult indications ranging from toothache or backache to chronic conditions like osteoarthritis. It is available in multiple formulations, including oral suspensions, chewable, and even orally disintegrating tablets. Many prescription medications contain acetaminophen.

Acetaminophen is one of the most used medications and is considered both effective and safe when taken at recommended doses. However, If too much acetaminophen is consumed, it can cause serious adverse effects, including both kidney and liver damage. Acetaminophen consumption has become the most common cause of acute liver disease. An acetaminophen overdose may occur either intentionally or unintentionally, given the number of medications available containing combinations. It’s essential to be aware of other medications that may contribute to the nephrotoxicity and hepatotoxicity side effects observed with acetaminophen consumption, as well as drug interactions that impact the metabolism of acetaminophen.

Key takeaways:

• Acetaminophen interactions generally occur due to alterations in metabolic routes, which increase the conversion of acetaminophen to the hepatotoxic metabolite NAPQI, scenarios of glutathione depletion, which decrease glucuronidation metabolism of NAPQI, and exertion of additive hepatotoxic effects independent of the individual agents. 
• Symptoms associated with acetaminophen toxicity, which may represent developing or present liver failure, include upset stomach, nausea, vomiting, loss of appetite, and jaundice.
• In the event of an acetaminophen interaction with concerns of acute toxicity, be it an accidental or intentional overdose, contact the national poison control hotline at 800-222-1222 to be connected to a poison control center in your area. 
• In specific interactions, acetaminophen may diminish other medications’ therapeutic effects when taken concurrently. 

Acetaminophen-drug interactions

Acetaminophen can interact with many medications, including those that may independently cause liver failure and those that alter the metabolism of acetaminophen, resulting in an increased risk of its toxic metabolites and effects. Acetaminophen may also blunt the effects of other medications that impact the immune system, including some medicines used to manage cancer diagnoses and even the immune response following vaccinations.

Antiepileptics

Acetaminophen’s hepatic metabolism may be increased by certain antiepileptics, including carbamazepine, fosphenytoin, phenytoin, phenobarbital, and primidone. In addition to the effect on metabolism on acetaminophen, these antiepileptics may also increase the formation of the hepatotoxic metabolite N-acetyl-p-benzoquinone (NAPQI), which increases the risk of hepatotoxicity by exceeding glutathione binding capacity. The concerning aspect of this potential interaction is that it can take place following generally considered low concentrations of acetaminophen, complicating a timely diagnosis and management of acetaminophen toxicity. Given these concerns, individuals taking these antiepileptics requiring pain relief or fever-reducing drugs should be monitored for increased hepatotoxicity and reduced acetaminophen efficacy; it may be best to avoid the combinations altogether or seek medical advice for recommendations of alternatives to decrease the risk of hepatotoxicity. 

Acetaminophen may decrease the serum concentration of the antiepileptic drug lamotrigine through a different mechanism. The mechanism for this interaction remains undefined, but evidence suggests that increased lamotrigine metabolism occurs when taken with acetaminophen. In one evaluation, the clearance of a lamotrigine metabolite increased by an average of 45%. The extent to which small and single or intermittent doses interact with lamotrigine remains undefined. However, when repeated doses of a pain medication/fever reducer are necessary, individuals on lamotrigine should consider an alternative to acetaminophen.

Vitamin K antagonists

Warfarin, in the class of vitamin K antagonists, may increase the risk for enhanced anticoagulation effects when individuals take it with daily doses of acetaminophen greater than approximately 2 grams daily for multiple consecutive days. Individuals should be warned of the increased risk of bleeding if starting acetaminophen or if the dose is increased or decreased. One review of this interaction recommends that individuals consuming 2 grams per day or more of acetaminophen for 3 or more consecutive days should have their monitoring of warfarin increased 3 to 5 days after the first dose of acetaminophen. While the precise mechanism remains unknown, there are likely multiple contributing mechanisms related to alterations in metabolism and reductions in concentrations of clotting factors.

Metyrapone

Metyrapone is used to diagnose certain problems of the adrenal glands, which are located near the kidneys and produce cortisol to help the body respond to illness or stress. In some cases, metyrapone is used off-label in the treatment of Cushing syndrome. Cushing syndrome is defined as prolonged and increased circulating levels of plasma, most often caused by corticosteroid use. Metyrapone can increase the acetaminophen serum concentration to shift the metabolism toward the route that produces its hepatotoxic metabolite, NAPQI. Metyrapone and acetaminophen should not be used in conjunction chronically, and receipt of one medication is considered a contraindication to receiving the other. 

Probenecid 

Probenecid is a medication that can be used for a few different indications. It is sometimes used to prevent episodes of gout attacks, and side effects from the antiviral prescription drug cidofovir, as well as an enhancer of concentrations of some antibiotics in treating certain infections. Probenecid may also increase the serum concentrations of acetaminophen through reduced clearance and limit the formation of a major non-toxic metabolite of acetaminophen, which may increase the formation of the toxic NAPQI metabolite. The combination of acetaminophen and probenecid should be limited whenever possible to minimize toxic adverse effects. 

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) are a class of oral prescription medications used for cancer treatment. There are over 50 TKIs approved by the Food and Drug Administration (FDA), with the ongoing rapid development of new drugs every year. Certain TKIs have demonstrated interactions with acetaminophen, specifically enhancing the hepatotoxic effects of the TKIs themselves. Likewise, the TKIs may also increase the acetaminophen serum concentration, a 2-way, additive interaction. Limiting acetaminophen ingestion when taking TKIs known to cause liver damage independently is an important approach to minimize this serious side effect. Alternative pain management nonprescription medications can be discussed with a healthcare provider.

Tyrosine kinase inhibitors that have demonstrated an interaction with acetaminophen include:

• Dasatinib
• Imatinib
• Sorafenib
• Sunitinib

Immune Checkpoint Inhibitors (Anti-PD-1, Anti-PD-L1, and Anti-CTLA 4)

Acetaminophen may diminish the therapeutic effect of immune checkpoint inhibitors. An analysis of 3 separate studies of patients treated with immune checkpoint inhibitors with exposure to acetaminophen and detectable plasma acetaminophen levels (compared with patients without detectable acetaminophen levels) demonstrated a decrease in overall survival, progression-free survival, or an objective response rate. The interaction mechanism remains unknown, but the authors of the analysis suggest that acetaminophen may decrease the antitumor effects of T-cells. While acetaminophen use may be periodically required in cancer patients receiving these medications, further data should be analyzed to elucidate this possible interaction better. If alternatives to acetaminophen can be employed, they should be recommended. 

Anti-PD-1, Anti-PD-L1, and Anti-CTLA 4 immune checkpoint inhibitors include: 

• Atezolizumab 
• Avelumab
• Cemiplimab
• Dostarlimab
• Durvalumab
• Ipilimumab
• Nivolumab 
• Pembrolizumab
• Retifanlimab
• Tremelimumab

Vaccines

Acetaminophen may diminish the therapeutic effect of vaccines when given prophylactically before or during vaccine administration. Healthy infants randomized to receive three doses of prophylactic acetaminophen after vaccine administration displayed a statistically significantly lower antibody response than non-acetaminophen (placebo) group patients. Other studies have replicated the findings that prophylactic acetaminophen led to reduced antibody responses. However, studies have concluded that using acetaminophen after vaccination to treat fever or pain did not affect antibody response. The Advisory Committee on Immunization Practices (ACIP) recommends avoiding acetaminophen before or during administration to minimize this potential risk of decreased immune response. However, after vaccine administration, ACIP recommends use for fever treatment and local pain. It is thought that the mechanism of this interaction involves acetaminophen suppression of the inflammatory response, which is considered an essential component of the host response. 

It’s important to note that these lists are not all-inclusive. Always check with a healthcare professional for any drug-drug interactions. 

Other acetaminophen interactions

Acetaminophen is generally considered a very safe medication, which in part lends to its availability as a nonprescription drug. It is important, however, to be aware of the appropriate doses for consumption. In 2002, the FDA Nonprescription Advisory Committee (NDAC) reviewed safety data related to its use. It made recommendations to educate consumers better to reduce the risk of liver damage since the dose of acetaminophen varies from product to product. The maximum daily dose for a healthy adult weighing at least 150 pounds is 4 grams, but it’s best to take the lowest amount necessary and stay closer to 3 grams per day as the maximum dose. In certain scenarios, this maximum daily dose differs. 

Acetaminophen and alcohol 

Published data suggest an elevated risk of acetaminophen hepatotoxicity in some patients who have alcohol use disorder. Evidence supports that acetaminophen administered during certain times to alcoholics can result in an increase of 22% in the mean formation of the toxic metabolite NAPQI. Generally, a dose or two of acetaminophen around the time of a drink of alcohol is not much to be alarmed about. However, for those consuming three or more alcoholic beverages per day, always ask a healthcare professional whether acetaminophen is safe, and the maximum daily dose should not be exceeded. In those chronically consuming high levels of alcohol and taking acetaminophen at the clinically recommended dose limits of 3 to 4 grams per day, concomitant alcohol and acetaminophen can cause additive liver damage. 

Acetaminophen and liver disease

Acetaminophen can be safe even for people with liver disease when directed. While we know healthy individuals should not exceed 4 grams per day for no more than 3 to 5 days, patients with liver disease should limit their daily amount to 2 grams per day, possibly even less. Individuals with liver disease should consider the effects of acetaminophen and seek further health information from a healthcare professional. 

How to minimize acetaminophen interactions

Always bring a complete list of medications being taken, including supplements, when visiting the doctor. Provide this list so that a thorough review and drug information assessment can be performed to help minimize the risk of drug interactions. Anytime a new medication has begun, and new signs or symptoms arise, reviewing this list with a healthcare professional is best. Make sure to take the lowest dose of acetaminophen possible for the shortest duration possible. 

When to talk to a healthcare provider about acetaminophen interactions

This article is only a partial list of acetaminophen interactions. Be mindful of the risk of additive side effects and direct drug interactions, which may occur when acetaminophen is used in combination with prescription and over-the-counter medications. When acetaminophen is needed, speak with a medical practitioner immediately so that a thorough assessment of drug, food, and medical conditions interactions may occur, and an appropriate monitoring plan can be implemented.